This proposal addresses a fundamental characteristic of tuberculosis pathogenesis - necrotization of tuberculosis lung lesions and provides a mechanistic basis for host-directed therapies that specifically target tissue damage caused by intracellular bacterial pathogens in susceptible individuals. Lung granulomas is a critical site o host interactions with Mycobacterium tuberculosis (M.tb). M.tb is able to establish a niche in host granulomas, where it may either persist or cause destruction, ultimately leading to cavitation of lung lesions and spread to new hosts via aerosol. However, in-depth mechanistic analysis of host factors that shape the lung granulomas has been limited due to a lack of adequate animal models. Little is known about local tissue-specific host factors that drive granuloma dynamics and pathology in the lungs of susceptible, but immunocompetent, hosts. Using forward genetic analysis in mice, we have developed a genetically standardized and well- characterized mouse model of human-like necrotic granulomas. In this model, a single genetic locus, sst1, is responsible for exuberant immunopathology and necrotization of granulomas specifically in the lung, even though known mechanisms of systemic immunity are intact. Upon activation, macrophages of the sst1 susceptible (sst1S) genotype exhibit hyperactivation of type I interferon (IFN-I) pathway leading to enhanced stress response and accelerated death in vitro. We hypothesize that over-activation of the IFN-I network may, as well, account for the necrotization of granulomas in vivo in the lungs of sst1S mice after M.tb infection. To test this hypothesis, we will 1) compare the dynamics of necrotizing (sst1S) and non-necrotizing (sst1R) pulmonary TB granulomas using multi-modal imaging to define stages of TB granuloma evolution and identify prognostic imaging biomarkers of necrotization; 2) characterize recruitment, maturation and death of IFN? producing cells in pulmonary TB granulomas; 3) evaluate effects of type I interferon (IFN-I) pathway inhibition on progression and maintenance of necrotic lung granulomas using temporal IFN-I receptor blockade with specific antibodies and small molecule inhibitors. Understanding the dynamics and mechanisms of necrotic granuloma formation and maintenance in genetically susceptible hosts, is essential for the development of rational host-directed therapies for TB. We will determine if pharmacological inhibition of specifi IFN-I mediated pathways can be used to prevent or treat necrotic TB granulomas. This would be an attractive therapeutic strategy in TB patients, as these inhibitors would specifically target harmful pathways leading to immunopathology, but would not compromise essential effector mechanisms of anti-mycobacterial immunity.